Variant: NM_000156.6:c.590T>C

CA402990982

Gene: GAMT

Condition: guanidinoacetate methyltransferase deficiency

Inheritance Mode: Autosomal recessive inheritance

UUID: 70289cf1-f13c-4317-b172-1ab3d6434b82

Approved on: 2023-05-25

Published on: 2023-05-25

HGVS expressions

NM_000156.6:c.590T>C
NC_000019.10:g.1397480A>G
CM000681.2:g.1397480A>G
NC_000019.9:g.1397479A>G
CM000681.1:g.1397479A>G
NC_000019.8:g.1348479A>G
NG_008283.1:g.18597A>G
NG_009785.1:g.9074T>C
ENST00000252288.8:c.590T>C
ENST00000640164.1:n.423T>C
ENST00000640762.1:c.521T>C
ENST00000252288.6:c.590T>C
NM_000156.5:c.590T>C

Likely Pathogenic

• Met criteria codes: PS3_Supporting PP3 PP4_Strong PM2_Supporting

Expert Panel

Cerebral Creatine Deficiency Syndromes VCEP

Criteria Specification Information

Criteria Specification: ClinGen Cerebral Creatine Deficiency Syndromes Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines for GAMT Version 1.1.0

Evidence submitted by expert panel

Cerebral Creatine Deficiency Syndromes VCEP

The NM_000156.6:c.590T>C variant in GAMT is a missense variant predicted to cause substitution of leucine by proline at amino acid 197 (p.Leu197Pro). This variant has been detected in two unrelated individuals with GAMT deficiency. Of those individuals, one was compound heterozygous for the variant and a likely pathogenic variant, c.526delG, in unknown phase (PMID: 19288536) and one individual was homozygous for the variant (PMID: 16293431) (0.75 points total) (PM3_Supporting). This variant is absent in gnomAD v2.1.1 (PM2_Supporting). One patient with this variant had elevated GAA with low creatine in plasma and elevated GAA with low creatine in urine (PMID: 19288536) and another patient with this variant had elevated GAA with low creatine in plasma, elevated GAA with low creatine in urine, absent creatine peak on brain MRS (PMID: 16293431) (PP4_Strong). Expression of the variant in GAMT-deficient human fibroblast cell line resulted in <5% wild type GAMT activity indicating that this variant may impact protein function (PMID: 24415674) (PS3_Supporting). The computational predictor REVEL gives a score of 0.925 which is above the threshold of 0.75, evidence that correlates with impact to GAMT function (PP3). There is no ClinVar entry for this variant. In summary, this variant meets the criteria to be classified as likely pathogenic for GAMT deficiency based on the ACMG/AMP criteria applied, as specified by the ClinGen Cerebral Creatine Deficiency Syndromes Variant Curation Expert Panel (Specifications Version 1.1,0): PS3_Supporting, PM2_Supporting, PM3_Supporting, PP4_Strong, PP3. (Classification approved by the ClinGen Cerebral Creatine Deficiency Syndromes Variant Curation Expert Panel on May 25, 2023)

Met criteria codes

• PS3_Supporting: Expression of the variant in GAMT-deficient human fibroblast cell line resulted in <5% wild type GAMT activity indicating that this variant may impact protein function (PMID: 24415674) (PS3_Supporting)
• PP3: The computational predictor REVEL gives a score of 0.925 which is above the threshold of 0.75, evidence that correlates with impact to GAMT function (PP3).
• PP4_Strong: One patient with this variant had elevated GAA with low creatine in plasma and elevated GAA with low creatine in urine (PMID: 19288536) and another patient with this variant had elevated GAA with low creatine in plasma, elevated GAA with low creatine in urine, absent creatine peak on brain MRS (PMID: 16293431).
• PM2_Supporting: This variant is absent in gnomAD v2.1.1 (PM2_Supporting).